The University of Pennsylvania ACTU proposes enrolling 125 new patients each year, 75 at the Univ of Penn, and 50 at Thomas Jefferson University. Expected enrollment includes 10-20% women and 30-40% minorities based on demographics of the epidemic in Philadelphia. Half of the patients are recruited from our practices, the remainder from community sources. Dr. Rob MacGregor serves as P.I. at the University of Pennsylvania site, Drs. Roger Pomerantz and Stephen Hauptman share responsibility at Thomas Jefferson University, and Dr. Harvey Friedman serves as overall P.I. Each site has its own pharmacy plan, study coordinator, study nurses, and data entry clerk. Shared resources include common virology and immnology laboratories and a data manager responsible for quality assurance and quality control at both sites. Investigators from the two institutions meet monthly to review accrual targets and scientific achievements, and meet every two months with the Community Advisory Board and every four months with the Scientific Advisory Board. Potential contributions from investigators in our unit to the Scientific Agenda of the ACTG include the following. HIV Disease: Dr. Roger Pomerantz chairs the gene therapy working group. His research uses genetic approaches to inhibit HIV-1 replication, including efforts at "intracellular immunization" with fragments of immunoglobulin molecules that bind to HIV-1 proteins. Through this research and his role as Chair, he is likely to advance ACTG efforts aimed at new strategies to limit replication of HIV-1. Dr. Harvey Friedman's research examines mechanisms of virus evasion of immune responses and the role of HIV-1 vif in transmission of infection. These investigations are relevant to the scientific goal of applying laboratory techniques to explore HIV-1 pathogenesis. Dr. Ian Frank serves on the Combination Therapy Working Group, and is an active participant in antiretroviral clinical trials. He recently submitted a concept proposal to combine RT inhibitors with hydroxyurea, a drug that reduces intracellular dNTP pools, as a novel approach to antiretroviral therapy. Complications of HIV Disease Dr. Rob MacGregor, a member of the Mycobacterial Bacterial Pathogens Study Group, has participated in studies that help define improved methods for prevention and treatment of OIs, particularly mycobacterial infections. Immunology and Immune-Based Therapy Dr. Hedy Teppler, a member of the General Immune Modulation Working Group, has developed two protocols. One evaluates thalidomide as an inhibitor of tumor necrosis factor-alpha, the other examines IL-2 to preserve CD4 cell number and improve function.